SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis
Menée in vitro, cette étude met en évidence un mécanisme par lequel la désuccinylase SIRT5 stabilise la glutaminase mitochondriale et favorise la tumorigenèse mammaire
The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated in cancer cells, and a GLS-selective inhibitor is being evaluated in clinical trials. Previous screens identified succinylated lysine residues on GLS, but the functional consequences of these posttranslational modifications have remained unclear. Here, we report that the mitochondrial desuccinylase SIRT5 stabilizes GLS. Both GLS and SIRT5 are upregulated during cellular transformation, and high expression of SIRT5 in human breast tumors correlates with poor patient prognosis. Mechanistically, SIRT5-mediated desuccinylation of residue K164 protects GLS from ubiquitination at K158 and from subsequent degradation. These findings reveal an important role for SIRT5 in mammary tumorigenesis and establish a posttranslational mechanism regulating GLS levels. Collectively, they support further investigation of SIRT5 as a potential therapeutic target.The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated during tumorigenesis and is being evaluated as a target for cancer therapy. GLS catalyzes the hydrolysis of glutamine to glutamate, which then supplies diverse metabolic pathways with carbon and/or nitrogen. Here, we report that SIRT5, a mitochondrial NAD+-dependent lysine deacylase, plays a key role in stabilizing GLS. In transformed cells, SIRT5 regulates glutamine metabolism by desuccinylating GLS and thereby protecting it from ubiquitin-mediated degradation. Moreover, we show that SIRT5 is up-regulated during cellular transformation and supports proliferation and tumorigenesis. Elevated SIRT5 expression in human breast tumors correlates with poor patient prognosis. These findings reveal a mechanism for increasing GLS expression in cancer cells and establish a role for SIRT5 in metabolic reprogramming and mammary tumorigenesis.